Okada Motohiro, Fukuyama Kouji, Okubo Ruri, Shiroyama Takashi, Ueda Yuto
Department of Neuropsychiatry, Division of Neuroscience, Graduate School of Medicine, Mie University, Tsu 514-8507, Japan.
Pharmaceuticals (Basel). 2019 Oct 6;12(4):149. doi: 10.3390/ph12040149.
Lurasidone is an atypical mood-stabilizing antipsychotic agent with unique receptor-binding profile, including 5-HT7 receptor (5-HT7R) antagonism. Effects of 5-HT7R antagonism on transmitter systems of schizophrenia and mood disorders, however, have not been well clarified. Thus, this study examined the mechanisms underlying the clinical effects of lurasidone by measuring mesocortical serotonergic transmission. Following systemic and local administrations of lurasidone, MK801 and 5-HT receptor modulators, we determined releases of 5-HT in dorsal raphe nucleus (DRN), mediodorsal thalamic nucleus (MDTN) and medial prefrontal cortex (mPFC) and γ-aminobutyric acid (GABA) in DRN using multiprobe microdialysis with ultra-high-performance liquid chromatography (UHPLC). Serotonergic and GABAergic neurons in the DRN are predominantly regulated by inhibitory 5-HT1A receptor (5-HT1AR) and excitatory 5-HT7R, respectively. Lurasidone acutely generates GABAergic disinhibition by 5-HT7R antagonism, but concomitant its 5-HT1AR agonism prevents serotonergic hyperactivation induced by 5-HT7R inhibition. During treatments with 5-HT1AR antagonist in DRN, lurasidone dose-dependently increased 5-HT release in the DRN, MDTN and mPFC. Contrary, lurasidone chronically enhanced serotonergic transmission and GABAergic disinhibition in the DRN by desensitizing both 5-HT1AR and 5-HT7R. These effects of lurasidone acutely prevented MK801-evoked 5-HT release by GABAergic disinhibition via N-methyl-D-aspartate (NMDA)/glutamate receptor (NMDA-R)-mediated inhibition of 5-HT1AR function, but enhanced MK801-induced 5-HT release by desensitizing 5-HT1AR and 5-HT7R. These results indicate that acutely lurasidone fails to affect 5-HT release, but chronically enhances serotonergic transmission by desensitizing both 5-HT1AR and 5-HT7R. These unique properties of lurasidone ameliorate the dysfunctions of NMDA-R and augment antidepressive effects.
鲁拉西酮是一种非典型的心境稳定型抗精神病药物，具有独特的受体结合特征，包括对5-羟色胺7受体（5-HT7R）的拮抗作用。然而，5-HT7R拮抗作用对精神分裂症和心境障碍递质系统的影响尚未完全阐明。因此，本研究通过测量中皮质5-羟色胺能传递，探讨了鲁拉西酮临床疗效的潜在机制。在对鲁拉西酮、MK801和5-羟色胺受体调节剂进行全身和局部给药后，我们使用超高效液相色谱（UHPLC）多探针微透析法测定了中缝背核（DRN）、丘脑背内侧核（MDTN）和内侧前额叶皮质（mPFC）中5-羟色胺（5-HT）的释放以及DRN中γ-氨基丁酸（GABA）的释放。DRN中的5-羟色胺能和GABA能神经元分别主要受抑制性5-羟色胺1A受体（5-HT1AR）和兴奋性5-HT7R的调节。鲁拉西酮通过5-HT7R拮抗作用急性产生GABA能去抑制作用，但同时其5-HT1AR激动作用可防止5-HT7R抑制诱导的5-羟色胺能过度激活。在DRN中用5-HT1AR拮抗剂治疗期间，鲁拉西酮剂量依赖性地增加了DRN、MDTN和mPFC中5-HT的释放。相反，鲁拉西酮通过使5-HT1AR和5-HT7R脱敏，长期增强了DRN中的5-羟色胺能传递和GABA能去抑制作用。鲁拉西酮的这些作用通过N-甲基-D-天冬氨酸（NMDA）/谷氨酸受体（NMDA-R）介导的5-HT1AR功能抑制，急性地通过GABA能去抑制作用防止MK801诱发地5-HT释放，但通过使5-HT1AR和5-HT7R脱敏增强了MK801诱导的5-HT释放。这些结果表明，鲁拉西酮急性时不影响5-HT释放，但长期通过使5-HT1AR和5-HT7R脱敏增强5-羟色胺能传递。鲁拉西酮的这些独特性质改善了NMDA-R的功能障碍并增强了抗抑郁作用。
